Genomics and immunobiology behind celiac disease

The development of celiac disease requires a genetic component, namely human leukocyte antigen (HLA) DQ2 or DQ8 alleles. Of the celiac patients around 95% carry the DQ2 and almost all the rest the DQ8 allele. However, at the population level, approximately 40% of individuals possess these alleles, while only subset of these individuals acquire the disease during their lifetime making the determination of the HLA-type diagnostically useful for exclusion of celiac disease. In addition to HLA, other genetic variants associated with celiac disease have been identified in genome-wide association studies (GWAS) and with candidate-gene approaches. However, the precise contribution of these genetic variants is not currently well understood and studies addressing this aspect are ongoing. The genetic predispositions are not sufficient to explain the development of celiac disease. We have shown that the intestinal microbiota differs between different manifestations of celiac patients and that treated celiac patients with persistent symptoms have intestinal dysbiosis despite a strict gluten-free diet. Thus, in addition to gluten, there must be other environmental triggers, such as microbial infections or intestinal dysbiosis that contribute to disease progression.

We have also addressed the biological functions of the celiac disease-specific antibodies in the pathogenesis. Our results show that the antibodies modulate epithelial and endothelial cell biology for instance by enabling the passage of gliadin peptides across the epithelium and increasing vascular permeability. In addition, when injected into mice the celiac antibodies induce a condition mimicking early developing celiac disease. The studies focusing on the pathogenetic role of the celiac disease-specific antibodies will continue.